Infections in complex physical environments: Life and death in the sinuses

Long-term infections and inflammatory conditions are complex host-pathogen responses that are often poorly understood because of the multi-scale nature of the response and numerous physical and biological factors that are involved. Building experimental and conceptual frameworks is necessary to gain a predictive understanding of such complex systems and to link the local interactions and responses to overall emergent behaviour. This approach, which requires an interdisciplinary effort, has the potential to offer unprecedented insights at the life sciences/physics interface. Here we propose to study chronic rhinosinusitis (CRS) as a model of such an approach. CRS is defined as an inflammation of the nose and paranasal sinuses present for more than 12 weeks and affecting 5-12% of the general population. CRS not only significantly reduces the quality of life of patients but also incurs very high healthcare costs. Pathogenesis of CRS is attributed to a combination of multiple 'biological' and 'physical' factors, i.e. the multifactorial aetiology results from a dysfunctional interaction between various environmental factors and the host immune system. Furthermore, bacterial growth is a significant factor in CRS, but its precise role has been difficult to elucidate. The "system" we propose to study consists of bacterial communities in their host environment, i.e. models of the host sinus cavity, characterised by the shape and geometry, the mucosal response of the innate immune cells, linked to the chemokine expression and inflammatory response against the infection, and the role of goblet and ciliated epithelial cells that constantly generate and displace a mucus lining, ordinarily an effective defence against microbial infections. The host sinus microenvironment is such a unique combination of dynamic physical, chemical and biological factors that understanding it requires a multi-disciplinary approach. With a clinician in the team, our conceptual and experimental approaches to understanding this system will aid in treating CRS. We also expect that many results obtained here will be applicable to a wide variety of other complex living systems, where flow, microbes and host response interact, e.g. gut, lungs or urinary tract. As microbes occupy every exposed surface of their host multi-cellular organisms, this approach can help pave the way for an interdisciplinary understanding of one of the most important interactions in all of biology.